The goal of this application is to test two hypotheses: a) T. pallidum isolates contain populations of organisms with enhanced ability to invade the CNS; and b) The capacity for neuroinvasion is conferred by expression of specific surface proteins. Specifically, the Aims of this project are: 1) Compare the neuroinvasive capacity of T. pallidum subpopulations within strains using in vivo and in vitro models; 2) Establish highly neuroinvasive T. pallidum populations; 3) Demonstrate the direct involvement of surface proteins in mediating neuroinvasion in vivo; 4) Determine which tprs are most frequently transcribed and expressed by T. pallidum organisms that are neuroinvasive; 5) Identify proteins that are preferentially expressed by neuroinvasive organisms; 6) Investigate the direct involvement of the Tpr proteins and the proteins identified in Specific Aim 5 in neuroinvasion using in vitro and in vivo models. The studies proposed in this application may ultimately contribute to development of a vaccine for syphilis and may lead to the ability to identify patients at the highest risk for neuroinvasion. These investigations are most applicable to persons who are also infected with HIV-1, as they are at greatest risk for syphilis and neurosyphilis.